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Abnormal uterine bleeding: a focus on

polycystic ovary syndrome
Martha Hickey, Krish Karthigasu & Sweta Agarwal
Abnormal uterine bleeding imposes major medical, social and financial problems for women, their
families and the health services. Abnormal uterine bleeding refers to the regularity, frequency,
duration and volume of bleeding. Irregular menstrual bleeding is most common at the extremes
of reproductive life, in the initial 1218months after menarche and 56years before the menopause
begins. In Australia, the estimated cost of investigating and managing heavy menstrual bleeding
alone is approximately AUS $6million per annum. This article addresses the common causes of
irregular bleeding in pre- and peri-menopausal women and presents an investigational approach.

Abnormal uterine bleeding (AUB) is that

which is irregular, heavy and/or prolonged [1] .
Disturbances of menstrual bleeding are a major
medical, social and financial problem for women,
their families and the health services. In many
developed countries, AUB is the most common
reason for women to consult their general practitioner or gynecologist and is responsible for
as many as a third of all outpatient visits to a
gynecologist [2] . A total of 40% of British women
believe their bleeding to be excessive or heavier
than usual and 10% complain of prolonged
bleeding [3] . This translates into nearly 4million
Australian women. Irregular menstrual bleeding
is most common at the extremes of reproductive
life, in the initial 1218months after menarche
and 56years before the menopause begins [4] .
In Australia, the estimated cost of investigating and managing heavy menstrual bleeding alone is approximately AUS $6 million
per annum [1] . AUB refers to the regularity,
duration and volume of vaginal bleeding [5] .
The causes of AUB are poorly understood and
this has considerably limited the development
of medical treatment options. Approximately
35% of Australian women eventually undergo
hysterectomy, which represents a major additional health cost, the majority for menstrual
disorders[6] .
A confusing, inconsistent and overlapping
array of terms has evolved to describe abnormal
frequency, duration or volume of uterine bleeding [5] . For this reason, the general term abnormal uterine bleeding is often used instead of
terms such as polymenorrhea, menorrhagia and
oligomenorrhea. Dysfunctional uterine bleeding (DUB) is not a generic term for AUB, but is
excessively heavy, prolonged or frequent bleeding
of uterine origin that is not due to pregnancy or
to recognizable pelvic or systemic disease.
10.2217/WHE.09.20 2009 Future Medicine Ltd

Normal menstrual cycle

The normal menstrual cycle results from a

complex feedback system involving the hypothalamus, pituitary, ovary and uterus. The key
aspects of menstruation that may be altered in
AUB include [5] :
Cycle regularity: irregular, regular or absent
Frequency of menstruation: frequent, normal
or infrequent
Duration of menstrual f low: prolonged,
normal or shortened
Volume of menstrual flow: heavy, normal
or light.
Large population studies have defined the normal range of menstrual cycle length, duration
of bleeding and amount of blood loss [4] . The
average adult menstrual cycle is 28days, with a
range between 21 and 35days, 46days of flow
and median blood loss of 30ml, with 80ml as
the upper limit of normal [1] .
This article will address common causes of
irregular bleeding in pre- and peri-menopausal
women and will present an investigational
approach. Bleeding that is too frequent (a cycle
of less than every 21days) or infrequent (a cycle
of more than every 36days) will be discussed.
Pregnancy-related bleeding, primary and secondary amenorrhea, and investigation and causes of
heavy menstrual bleeding are beyond the scope
of this article.
Causes of menstrual irregularities in
adolescents: less than 20 years old

Author for correspondence:

School of Womens & Infants
Health, King Edward Memorial
Hospital, University of Western
Australia, Australia
Tel.: + 61 893 401 328
Fax: + 61 893 813 031
mhickey@meddent.uwa.edu.au

Keywords
abnormal uterine bleeding
adolescents dysfunctional
uterine bleeding hormonal
therapy menstrual irregularities
oral contraceptive pill
perimenopausal polycystic
ovarian syndrome progestogens
reproductive age

Irregular uterine bleeding in adolescent girls

may result from a wide spectrum of conditions including structural and endocrine
causes, and DUB. Pregnancy should always be
excluded as a cause. The most common cause is
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anovulation, which may be due to immaturity
of the hypothalamicpituitaryovarian (HPO)
axis (causing anovulatory DUB) or polycystic
ovary syndrome (PCOS).
In the initial months following menarche, the
normal negative feedback system between the
ovaries and anterior pituitary may malfunction.
If increasing levels of estrogen do not cause a
decrease in follicle-stimulating hormone (FSH)
secretion with subsequent suppression of estrogen secretion, multiple follicular recruitment
is stimulated and a dominant follicle does not
form. Under the influence of continued estrogen
secretion, the endometrium becomes excessively
thickened and, without adequate progesterone
levels, may slough, leading to heavy and irregular
bleeding. The heavy bleeding may be worsened
by an increase in prostacyclin synthesis in endometrial capillary epithelial cells under the influence of estrogen in the absence of progesterone.
This is because even an occasional ovulatory
period stabilizes and coordinates the sloughing
of the endometrium [79] . By definition, other
causes of irregular menses must be excluded
before a diagnosis of DUB can be made.
A common cause of chronic anovulation in
adolescents is PCOS, which should be considered in any adolescent with menstrual irregularity, clinical hyperandrogenism (hirsutism or
acne) or obesity. PCOS should also be considered
in adolescents who continue to have menstrual
irregularity 34years after menarche, even in the
absence of hirsutism or acne [9] . PCOS is diagnosed in the presence of two out of three of the
following: polycystic ovary appearance on ultrasound, clinical or biochemical hyperandrogenism
and anovulation [10] . The diagnosis of PCOS in
adolescence is problematic since many clinical
features (e.g., menstrual irregularity and acne)
are considered normal in adolescents. It was
previously considered that adolescent menstrual
irregularity represents normal maturation of the
HPO axis. However, there is increasing evidence
that this is not the case and that persistent menstrual irregularity in adolescence may be an early
presentation of PCOS. Menstrual irregularity
associated with normal reproductive development
is likely to resolve within the first 2years following menarche [11] . After this time, over 70% of
adolescents with irregular menses have clinical
and metabolic signs of PCOS [12] . By contrast,
adolescents aged 15 years with regular cycles
rarely develop menstrual irregularity in adulthood. Prospective cohort studies demonstrate
that the majority of adolescents with menstrual
irregularity continue to have irregular menses as
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adults, particularly those with a high BMI [13] or

persistent acne vulgaris [11] . Furthermore, menstrual irregularity in adolescents is commonly
associated with clinical, endocrine and ultrasound signs of PCOS [13] . The population incidence of PCOS in adolescence is not known, but
these studies suggest that it may be common and
is likely to be underdiagnosed. However, there is
increasing evidence that early diagnosis of PCOS
may confer clinical advantages. Other endocrine
causes of anovulation including thyroid dysfunction and hyperprolatinemia should be ruled out.
If clinically indicated, adrenal gland abnormalities, such as Addison disease, late-onset congenital adrenal hyperplasia or Cushing disease, may
need to be excluded [9,14,15] .
Significant weight loss, stress and exercise can
disturb the HPO axis and are not uncommon
causes of oligo/anovulation.
In those who are sexually active, endocervical
or pelvic infection may present with irregular
vaginal bleeding [16] .
Evaluation

The evaluation of the adolescent with AUB

begins with a careful history and physical examination. The physical examination further helps
to narrow the differential diagnosis and to direct
subsequent laboratory or radiographic evaluation.
History

The patients history should be obtained with

and without the patients guardian in the room.
Some girls prefer to be interviewed alone,
particularly if they have been sexually active.
Speaking with the patient alone, and with
her guardian present, facilitates obtaining a
thorough history and maintains the patients
confidentiality on subjects that she may not be
comfortable discussing in front of her parents.
A thorough menstrual history is critical for
the evaluation of patients with abnormal vaginal bleeding. This includes the age of menarche;
the characteristics of the first menstrual period;
the general frequency of periods; whether
periods have ever been regular; any associated
dysmenorrhoea; the timing, duration and quantity of bleeding during recent menstrual cycles;
and/or abnormal bleeding episodes. In girls who
describe a change in the menstrual pattern, it is
important to ask about other events that coincided with the change, such as stress, weight loss
or an increase in exercise levels. In patients with
irregular cycles, maintaining a menstrual calendar is very useful [17] . Patients should be asked
regarding any discharge from the breasts.
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Abnormal uterine bleeding: a focus on polycystic ovary syndrome

The sexual history should include information regarding contraception and condom use;
number of partners; new partners; history of
sexually transmitted infections or current symptoms (e.g., vaginal discharge and pelvic pain);
previous pregnancies or terminations; whether
sexual activity was forced or consensual; and
whether the adolescent has a history of sexual
abuse [18] .
The medical history should include information regarding systemic illness, hematologic
or renal disease, and current or recent medications. The doctor should enquire about weight
change, exercise regimens, su bstance use,
hirsutism, acne, visual changes and headaches.
A history of menstrual disorders in the
fa mily may suggest PCOS, or other familial
endocrine disorders.
Examination

The general examination should include: vital

signs, including pulse and blood pressure levels
[9,18,19] ; measurement of height and weight and
calculation of BMI; palpation of the thyroid
gland for enlargement or other abnormalities.
Evaluation for signs of androgen excess includes
hirsutism, acne, male pattern balding and signs
of acanthosis nigricans. If the prolactin is elevated the optic fundi should be examined and
visual field tested to evaluate the possibility of
a pituitary tumor. Tanner staging of the breasts
and assessment for galactorrheoa (bilateral
milky nipple discharge) should be conducted
as well as palpation of the abdomen for uterine
or ovarian mass.
As part of a secondary care approach, an
examination of the external genitalia should be
carried out whenever indicated. It is also important to look for nonuterine sources of bleeding
(e.g., perineal trauma, vulvar lesions and signs of
sexually transmitted infections). Girls who have
signs of perineal trauma should be questioned
privately regarding sexual abuse.
Pelvic examination

When indicated, a speculum examination

should be performed in order to rule out the
possibility of bleeding ectropion. A bimanual
examination is performed to assess for ovarian
or uterine masses and signs of pelvic inflammatory disease. If the history or symptoms
suggest pelvic infection, microbiological specimens should be collected from the cervix and
vagina. All girls who are sexually active should
have a Pap smear as per the national cervical
screening policy.
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Laboratory evaluation

This should include a pregnancy test, a complete blood count and measurement of thyroidstimulating hormone and prolactin levels. Blood
should be obtained during the early follicular
phase (days 26 of cycle) to test for PCOS. This
includes FSH, luteinizing hormone (LH), estradiol, total and free testosterone levels, dehydro
epiandrosterone sulfate (DHEAS) levels, sex
hormone-binding globulin, fasting lipid profile,
fasting plasma glucose level, 17 a-hydroxyprogesterone (elevated in late-onset congenital
adrenal hyperplasia), fasting insulin level, and,
if indicated, urinary free cortisol to rule out
Cushings syndrome. In those with raised FSH,
karyotype should be carried out [20,21] .
Pelvic ultrasound

Pelvic ultrasound is indicated in all women,

transabdominal ultrasound is less sensitive and
specific than transvaginal ultrasound; however,
with optimum conditions may still be helpful. Pelvic ultrasound may also indicate uterine structural abnormalities and assist in the
diagnosis of PCOS [21] .
Management

The principal goals in managing irregular

uterine bleeding in adolescence are [17,22] :
Make the diagnosis
Correction of acute or chronic anemia
Return to a pattern of normal menstrual cycles
Prevention of recurrence
Prevention of long-term consequences of
anovulation
For those with anovulatory DUB, the primary
purpose of treatment is to stabilize endometrial
proliferation and promote regular shedding. All
patients with DUB are at risk for iron deficiency
anemia and should be monitored and treated
accordingly. The decision of whether to observe
girls with DUB or to treat them with hormonal
therapy depends upon patient and guardian considerations, as well as upon the severity and chronicity of the DUB. Cyclic progestogens or oral
contraceptive pills (OCP) may restore regular
bleeding patterns [17,19] . More than 90% of adolescents with DUB respond to hormonal therapy
[23,24] . Among those who do not, an alternative
diagnosis (e.g., bleeding disorder, PCOS, infection and uterine pathology) should be considered.
The treatment of DUB is guided by both
the hemoglobin level and whether the patient is
actively bleeding (Table1) [8,17] .

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Table1. Treatment of dysfunctional uterine bleeding.
Hemoglobin level

Treatment of dysfunctional uterine bleeding

Ref.

Hemoglobin level is greater than 12gm/dl and

patient is not actively bleeding

Reassurance
Maintain a menstrual calendar
Iron supplementation and re-evaluated in 36months

Hemoglobin level is between 10 and 12gm/dl

Hormone therapy
Iron supplementation
Hormone therapy is often a estrogenprogestin OCP. If the patient is
unable or unwilling to take daily OCPs and is not sexually active, an
alternative is to use intermittent oral medroxyprogesterone acetate or
norethindrone acetate, 10mg daily for 1014days every month or any
other progestogens with equivalent doses for three to six cycles. Cyclic
oral progesterone administered for 10days each month prevent the
actions of unopposed estrogen and stabilize the endometrium.
Withdrawal of progesterone each month allows organized sloughing of
the endometrium and clinically leads to predictable menses during the
perimenarchal, anovulatory period.
Re-evaluate at 3months or earlier if needed

Hemoglobin level is less than 10gm/dl

and patient is asymptomatic and not
actively bleeding

Estrogen-progestin OCP is indicated, together with iron

supplementation. Patients who have complaints of heavy bleeding may
have a better response to OCP that have a combination of estrogen and
progestin rather than to progestin-only preparations, since estrogen
provides hemostasis. Monophasic OCPs (i.e., pills that contain the same
dose of estrogen and progestin in each of the hormonally active pills)
with a minimum of 30g ethinyl estradiol should be used in order to
ensure a sufficient amount of estrogen is provided to prevent
breakthrough bleeding.

[29]

Treatment of dysfunctional uterine bleeding is guided by both hemoglobin levels and whether the patient is actively bleeding.
OCP: Oral contraceptive pill.

All patients with PCOS should be managed

with supportive therapy that encourages lifestyle
changes, the maintenance of a healthy weight,
exercise and diet. Menstrual irregularity should
be treated in patients with PCOS, since chronic
anovulation is associated with increased risk of
developing endometrial hyperplasia and carcinoma. The major treatment options for menstrual irregularity include progestin or OCPs.
Treatment of adolescents with PCOS using
oral hypoglycemics improves key clinical and
metabolic parameters, including hyperandrogenemia, insulin resistance, dyslipidemia and
obesity [2527] .
Oral contraceptive pills are the first-line endocrine treatment for women with the dermatologic or menstrual abnormalities of PCOS [28] .
OCPs induce regular menstrual periods with a
higher degree of reliability than any other form
of treatment. Progestin inhibits endometrial
proliferation, preventing hyperplasia. Estrogen
inhibits the activity of the hypothalamicpituatarygonadal axis, reducing ovarian androgen
production as well as increasing the sex hormone-binding globulin levels. OCP therapy normalizes the androgen levels in most cases within
18 to 21days. There are many choices of OCP,
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and it is recommended to use one that has a progestin with antiandrogenic or minimal androgenic activity. Menstrual irregularities in PCOS
can often be treated effectively with micronized
progesterone, 100200 mg daily at night for
710days [29] . This induces withdrawal bleeding
in most patients; however, some do not respond,
apparently because of an antiestrogenic effect
of androgen excess on the endometrium [30] .
Progestin therapy has the appeal of permitting
the detection of the emergence of normal menstrual cyclicity. The perimenarcheal girl who
responds well to progestin therapy can be maintained at approximately 6-week cycles to permit
the detection of spontaneous menses. Patients
must be informed that oral progestin dosed in
this way is not a means of contraception[20] .
Controversy persists regarding the use of oral
contraceptives in women with PCOS. OCPs provide cycle control, ameliorate androgenic symptoms and protect the endometrium. Nevertheless,
there are several potential disadvantages to the
use of OCPs for managing PCOS in adolescents.
In perimenarcheal girls with short stature who
have open epiphysis, OCPs are contraindicated
because they contain growth inhibitory amounts
of estrogen. OCPs may also be contraindicated
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in patients who are at risk for venous thrombosis. Patients may use OCPs as an excuse for
not losing weight. The patient may believe that
the treatment is curative and defer a definitive
diagnostic work-up. In addition, OCPs do not
permit conception if and when it is desired.
The long-term consequences of these agents on
fertility is unknown; concerns have been raised
that the immature adolescent neuroendocrine
system may have heightened the risk for postpill amenorrhea and infertility when exposed to
high-dose estrogen in early adolescence [31,32] .
However, this concern is based on observations
in other patient groups undergoing treatment
with high-dose estrogens during adolescence,
and its relevance to girls in PCOS in unclear.
Regarding PCOS, there are also some concerns
that the abnormal cardiovascular and metabolic
profiles commonly observed with PCOS may
be exacerbated by the OCP. Estrogens impair
carbohydrate tolerance, dose-dependently, as do
androgens and progestins of greater androgenicity. The composite effect of OCPs on glucose
tolerance and insulin sensitivity is determined
by the interplay of the above actions with the
insulin sensitivity of the individual, itself determined genetically, environmentally, as well as
by other factors such as puberty. The environmental influence may vary over time. OCPs
increase HDL and triglycerides, and this effect
varies with the progestin. Thus, in some PCOS
patients, such as the obese or pubertal, this additional metabolic risk should be considered when
OCPs are prescribed, and appropriate surveillance is advisable, as is concomitant use of agents
that modify these effects, such as metformin or
choosing the OCP mainly containing progestins
with antiandrogenic properties [33] .
Duration of therapy & follow-up

Girls treated with progestin therapy or combined hormonal contraceptives should return for
follow-up in 3 months. As a general rule, OCP
treatment should be continued until the patient
is gynecologically mature (5years postmenarchal) or has lost a substantial amount of excess
weight. At that point, withholding treatment for
a few months to allow recovery of suppression
of pituitarygonadal function and to ascertain
whether the menstrual abnormality persists
is usually advisable [29] . A menstrual calendar
should be maintained to monitor subsequent
episodes of irregular bleeding.
Long-term follow-up of girls with a history of
anovulatory cycles is essential. Chronic anovulation (greater than 23 years in duration) is
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associated with an increased risk of endometrial

hyperplasia and carcinoma, particularly if the
patient is obese or has a family history of endometrial, ovarian, breast or colon cancer. Obesity
promotes peripheral conversion of androgens
to estrogens, further enhancing endometrial
growth [34,35] .
Causes of menstrual irregularities in the
reproductive age group: 2040 years

Spontaneous irregular uterine bleeding is relatively uncommon in women who have previously
had regular cycles. Pregnancy should be considered as a cause in any sexually active women of
reproductive age. Women who are pregnant are
evaluated primarily for pregnancy-related causes
of bleeding; however, the possibility of a concurrent nonpregnancy-related etiology should
be kept in mind.
Polycystic ovary syndrome causes irregular
uterine bleeding in reproductive-aged women,
affecting approximately 6% of women in this
group [36] . Women with PCOS are adequately
estrogenized, since androgens can be converted
peripherally to estrogens even in the absence
of normal ovarian function, but low levels of
progesterone. Thus, constant mitogenic stimulation of the endometrium leads to endometrial
hyperplasia and unscheduled bleeding.
Endocrine disorders may be associated with
hormonal changes that affect ovulation and
cause irregular menstruation. Both hypo- and
hyper-thyroid activity are associated with AUB.
Women with hypothyroidism, even when subclinical, may have heavy or prolonged uterine
bleeding [37] . Hypothyroidism can cause hyperprolactinemia; this usually results in amenorrhea and galactorrhea, but women may develop
irregular menstrual bleeding prior to amenorrhea. Hyperthyroidism may cause anovulation
and irregular menstruation owing to alterations
in sex hormone-binding globulin [38] .
Cushings syndrome is a rare cause of menstrual irregularity [39] . Menstrual abnormalities correlate with increased serum cortisol and
decreased serum estradiol concentrations, but not
with serum androgen concentrations. The menstrual irregularities may be due to suppression of
secretion of gonadotropin-releasing hormone by
hypercortisolemia. High doses of corticosteroids
have a similar effect.
Hormone-secreting adrenal and ovarian tumors
are rare causes of menstrual irregularities. The
level or activity of sex hormones may be affected
by disorders unrelated to endocrine glands, such as
advanced liver or renal disease, that alter hormone

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metabolism or binding or suppress ovulation and
lead to menstrual irregularities. Liver disease can
affect both estrogen metabolism and synthesis
of coagulation factors, thereby potentially leading to both anovulation and bleeding diathesis;
in additon, chronic renal disease is associated
with both hypothalamicpituitarygonadal and
platelet dysfunction leading to characteristic
noncyclic bleeding pattern.
Stress, significant weight loss and exercise
can disturb the HPO axis and are not uncommon causes of irregular menstruation. Uterine
polyps are usually benign endometrial growths of
unknown etiology. Irregular bleeding is the most
frequent symptom, occurring in approximately
50% of symptomatic cases. Leiomyomas, also
known as fibroids, are the most common pelvic
tumors in women, occurring in approximately
25% of women of reproductive age. Intramural
and submucosal fibroids distort the endometrial
cavity, resulting in unusually heavy or prolonged
menstrual periods but those that form polyps
may present with irregular bleeding.
Reproductive-aged women with chronic
endometritis may present with AUB. Vague,
crampy lower abdominal pain may accompany
the bleeding. The most common finding on
physical examination is uterine tenderness or
cervical motion tenderness.

in warm weather and a goiter are symptoms and

signs indicating that hypothyroidism may be
present. A history of liver disease, excessive alcohol consumption, jaundice, hepatomegaly, spider hemangiomata, palmar erythema and ascites
are found in cases of advanced liver disease.
Symptoms of lower abdominal or pelvic pain,
fever, chills, shakes and a purulent discharge
suggest the presence of infection.
Examination

A general examination should be performed to

look for signs of systemic illness such as fever,
ecchymoses, an enlarged thyroid gland or evidence
of hyperandrogenism (e.g., hirsutism, acne, clitoromegaly or male pattern balding). Acanthosis
nigricans is highly suggestive of insulin resistance.
Galactorrhea may occur with hyperprolactinemia.
Physical examination of the external and
internal anatomy of the female genital tract is
crucial in identifying anatomic causes of AUB.
The physician should assess the size, contour,
and tenderness of the uterus. An enlarged uterus
with an irregular contour caused by discrete,
firm tumor masses are findings of a fibroid uterus
and physical findings of uterine or adnexal pain
on palpation or movement of the pelvic organs,
a sensation of increased warmth of the uterine
and adnexal structures, and purulent cervical
discharge is suggestive of pelvic infection.

Evaluation

The foundation of the evaluation of patients

with AUB is the history, the physical examination and the pelvic examination. Based
on the history and examination appropriate
investigations can be directed.
History

The patients history includes the onset, frequency, duration and the severity of the bleeding, changes from the usual menstrual pattern
and whether the bleeding is associated with pain.
Irregular bleeding needs to be distinguished
from intermenstrual bleeding; intermenstrual
bleeding is characterized by somewhat of a cycle
and bleeds in between while irregular bleeding
has a completely random pattern. Irregular
heavy periods are characteristic of anovulatory
bleeding. Age, parity, marital status, sexual history, previous gynecologic disease, contraceptive
history, medications and the dates of all past
pregnancies are all relevant to the evaluation of
women with AUB. Symptoms of pregnancy and
those related to reproductive tract disease are
important. Weight gain, marked fatigue, cold
hands and feet, constipation, failure to perspire
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Laboratory evaluation

A complete blood cell count is obtained from all

patients to check for anemia and platelet count
to rule out thrombocytopenia. Pregnancy should
be excluded modern urinary pregnancy tests
are highly sensitive [40] .
Assessment of cervical cytology (e.g., conventional or liquid based) should be performed as
per the national cervical screening guidelines
or if the cervical appearance is abnormal. After
pregnancy has been excluded as a cause, an endometrial biopsy should be performed in all women
over 45 years of age to rule out endometrial cancer or a premalignant lesion (e.g., endometrial
hyperplasia) [11] . Endometrial biopsy may be
considered in younger women who have risk factors for endometrial cancer: family or personal
history of ovarian, breast, colon or endometrial
cancer; tamoxifen use; chronic anovulation;
obesity; estrogen therapy; prior endometrial
hyperplasia; and diabetes [13] .
All women with irregular bleeding and in
the presence of clinical features suggestive of
hypo- or hyper-thyroidism have thyroid function tests. Thyroid-stimulating hormone is
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elevated in hypothyroidism and subnormal in

hyperthyroidism. Testing for Neisseria gonorrhea and Chlamydia trachomatis should be performed in patients at risk with intermenstrual or
postcoital bleeding or if there is cervicitis, purulent vaginal discharge and/or pelvic tenderness.
The vaginal discharge should also be evaluated
for trichomonads.
A prolactin level should be measured in all
women with irregular bleeding. Tests for PCOS
should be conducted, as well as tests to rule out
other endocrine disorders, which include FSH,
LH, estradiol, total and free testosterone levels,
DHEAS levels, sex hormone-binding globulin,
fasting lipid profile, fasting plasma glucose level,
17 a-hydroxyprogesterone (elevated in late-onset
congenital adrenal hyperplasia), fasting insulin
level, and if indicated, urinary free cortisol to
rule out Cushings syndrome.
If the history and physical examination identify specific individuals with AUB who are at
high risk for liver disease, liver function tests
should be obtained.
Pelvic ultrasound

The use of transvaginal ultrasonography of the

pelvis allows for the detection of gross pelvic
pathology and uterine fibroids. Ultrasound can
also assess endometrial thickness and characterize ovarian masses. In premenopausal women,
the examination should be performed on day 4,
5 or 6 of the bleeding cycle, when the endometrium is expected to be its thinnest (in reproductive-aged women, normal endometrial thickness
in the proliferative phase is 48mm and in the
secretory phase 814mm [41] . This allows better visualization of pathology in the uterine cavity. If structural abnormalities are suspected on
ultrasound examination, then these abnormalities can be further evaluated by saline infusion
sonography or hysteroscopy.
Management

The management of AUB depends on the etio

logy of the bleeding. In patients with identifiable
causes, treatment is targeted toward the cause [42] .
Cervical polyps can be removed in outpatient
clinic and endometrial polyps are removed surgi
cally by operative hysteroscopy. Symptomatic
uterine myomas are excised by operative hysteroscopy, myomectomy or hysterectomy.
Infections are treated with antibiotics that cover
the specific microorganisms involved.
The treatment of endometrial hyperplasia depends on whether atypia is present or
absent and whether the hyperplasia is simple or
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complex as well as on the patients fertility plans.

Management of hyperplasia is not discussed in
this article.
Underlying systemic disorders and endocrine
disorders need specific treatments. Once they are
treated the AUB is corrected.
Dysfunctional uterine bleeding is a diagnosis
of exclusion. The objectives of treating patients
with DUB are:
To control the bleeding
To prevent recurrences
To preserve fertility
To correct associated disorders
To induce ovulation in women who desire
to conceive
The age of the patient, the severity of the
bleeding, her number of children, the desire for
future fertility and the presence of associated
pelvic pathologic disorders, are factors that
influence the selection of therapy. Acute bleeding episodes can be managed with high-dose
estrogenprogestin therapy. To prevent recurrent episodes of anovulatory DUB, many physicians consider progestin therapy as the preferred treatment. Progestins stop endometrial
growth and support and organize an estrogenprimed endometrium. When progestin therapy
is withdrawn, an organized slough to the basalis
layer of the endometrium occurs, which permits
a rapid cessation of the bleeding when there
is adequate endogenous estrogen. A recent
Cochrane review has indicated that there was
insufficient evidence to demonstrate the effect
of either progestogen alone or in combination
with estrogens for DUB [43] .
In women with PCOS, treatment depends
upon the womans goals. In obese women, some
of the manifestations of PCOS can be ameliorated by weight loss. The desire for pregnancy
in the near future is also a major determinant
for choice of therapy. In women not desiring a
pregnancy, oral contraceptives are most commonly used for endometrial protection, since
they also provide contraception and cosmetic
benefit. The choice of oral contraceptive is
important because many progestins also possess
androgenic effects. Contraceptives containing
nonandrogenic progestins are preferred [4446] .
Drospirenone, an analogue of spironolactone
with unique antimineralocorticoid and antiandrogenic activities, is available for use in combination with ethinyl estradiol, thus improving
the antiandrogenic activity of an oral contraceptive for women who have PCOS [47] . A recent

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meta-analysis demonstrated a twofold increased
risk of myocardial infarction and ischemic
stroke in subjects taking low-dose oral contraceptives when compared with nonoral contraceptive users [48,49] . However, there is a controversy regarding the influence of OCP on insulin
metabolism as there have been several reports
that insulin sensitivity have been improved or
not modified by OCPs that mainly contain progestins with antiandrogenic property [50,51] . If
insulin resistance deteriorates in some PCOS
patients with the use of oral contraceptives, metformin may be an option in the treatment regimen. For women with PCOS who choose not to
or cannot take OCPs, an alternative treatment
for endometrial protection is intermittent progestin therapy. Women with PCOS who want
to become pregnant require further investigations and management of subfertility, which is
beyond the scope of this article.
Menstrual irregularities in
perimenopausal women: older than
40years
Causes

Menstrual bleeding irregularities are a hallmark

of the menopausal transition but frequently
result in women seeking gynecologic consultation [52] . Menopausal transition is a phase of
menstrual life when a persistent increase in variation between menstrual intervals occurs and
starts at approximately 40years of age across the
population. The median age at onset of transition is 45.5years, with a median duration of
4.8years [4] . Although an overwhelmingly probable marker of the normal transition, bleeding
irregularity raises concerns regarding possible
pregnancy, endometrial hyperplasia, or gynecologic malignancy and leads to diagnostic and
therapeutic interventions. Several longitudinal
studies have demonstrated that menstrual cycles
become more irregular in the years preceeding
the final menstrual period.
Anovulation is associated with both shortand long-cycle intervals as well as with both
short and long duration of the ensuing menstrual period. However, anovulatory cycles
were observed only after entry into early transition, which may thus provide an indication
of the occurrence of abnormal ovarian function, resulting from the reduction in ovarian
follicle number. The irregularity may result
from changes in the endocrinology of ovulatory cycles, or from the progressively increasing occurrence of anovulatory cycles. A total
of 20% of cycles were found to be anovulatory
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in this group of women, predominantly in the

early perimenopause. Short-cycle intervals are
more often observed early in the menopausal
transition. Thus, short intervals may be the first
sign of a woman entering the transition; longer
cycle intervals are observed later and are asso
ciated with higher FSH production, indicating
even fewer functioning ovarian follicles [53,54] .
Pregnancy should be considered in any female
with AUB even in perimenopausal age. Uterine
polyps are usually benign endometrial growths
of unknown etiology that are a common cause
of AUB in perimenopausal women, particularly
among tamoxifen users in whom the incidence
of endometrial polyps is approximately 32% [55] .
Thyroid function should also be investigated
since a low thyroid hormone level is more likely
to be associated with infrequent menses. In
women, there is an overall incidence of hypothyroidism of approximately between 6 and 4%
in the perimenopausal age range [14] .
Abnormal perimenopausal bleeding is associated with endometrial carcinoma in approximately 10% of cases; however, the highest risk
of endometrial carcinoma is among women who
weigh greater than or equal to 90kg and who
are 45years or older [56] .
Evaluation

The key to the diagnosis of AUB in perimenopausal women is a thorough history, physical
examination and pelvic examination directed at
all possible components of the differential diagnosis. In general, it is a mistake to use any hormonal therapy to slow or stop the bleeding until
cancer of the endometrium has been eliminated
as a possible cause. The development of flexible
suction catheters for office endometrial biopsy
has greatly facilitated the detection of endometrial hyperplasia, atypia and cancer; however,
unfortunately, we often only find what we look
for. The best way to detect endometrial cancer is
to consider it when making a diagnosis. Irregular
cycles in the late transition period or menopause
without vasomotor symptoms should be investigated [57] . The recommendation regarding
investigation of AUB from the Royal College of
Obstetricians and Gynaecologists is that women
over the age of 45 years should be investigated
with hysteroscopy and endometrial biopsy [17] .
Endometrial biopsy

Outpatient endometrial sampling can be performed in perimenopausal women presenting

with irregular bleeding. The reported sensitivity for detecting endometrial abnormality is
future science group

Abnormal uterine bleeding: a focus on polycystic ovary syndrome

approximately 85% with endometrial sampling

[19,23,58] ; however, hysteroscopy with selective
biopsy is more appropriate.
Transvaginal ultrasonography is useful
in determining endometrial thickness and
morphology as well as the regularity of the
endomyometrial border. Whilst the procedure is
well tolerated by patients, sessile or pedunculated
lesions of the endometrium and malignant disease cannot be definitively excluded [24] . Vaginal
sonohysterography is a modification of vaginal
ultrasound in which a small volume (515ml)
of saline is injected into the uterine cavity during
ultrasound examination. This enables irregularities of the endomyometrial border and the free
endometrial border to be more easily visualized
[59,60] . With regard to diagnostics of the uterine
cavity, recently a meta-analysis on the accuracy
of saline infusion sonography in women with
AUB reported a sensitivity and specificity of 0.95
and 0.88, respectively [61] .
Hysteroscopy

Hysteroscopy is considered an accurate gold standard in uterine cavity evaluation. Hysteroscopy

allows the operator to view the entire cavity and
take a directed biopsy. It is more specific and
sensitive than transvaginal ultrasound or blind
endometrial sampling [62] . In order to achieve
optimal visualization it is practical to schedule
diagnostic hysteroscopy in the follicular phase of
the cycle. It is both feasible and highly acceptable
in the majority of patients, giving a high detection rate for intrauterine pathology. The prevalence of intrauterine abnormalities in women
with AUB is approximately 46% at the time of
hysteroscopy from a recent meta-analysis. This
meta-analysis also indicates that diagnostic hysteroscopy has a sensitivity and specificity of 0.94
and 0.89, respectively [63] .
Management

A stepwise evidence-based approach to managing

irregular bleeding is recommended. Anovulatory
irregular bleeding requires endometrial protection with a combined OCP (COCP), the
levonorgestrel intrauterine system (LNG-IUS)
or cyclic oral progestins. Oral contraceptives,
especially the low-dose types, often represent
the best option to manage women presenting
with vasomotor symptoms in the late transition
period. They induce regularity of cycles and
control hot flushes [57] .
The LNG-IUS (Mirena, Bayer Schering
Pharma, Berlin, Germany) is a relatively new
treatment for AUB that remains effective for
future science group

Review

5years. It has been found to reduce menstrual

blood loss by 7497%, and approximately 50%
of women will be amenorrheic by 12months
[64,65] . Some studies have described the use of
the LNG-IUS among women in the late phase
of the menopausal transition, including those
with irregular menstrual cycles and vasomotor
symptoms. The LNG-IUS with estrogen supplementation in perimenopausal women suppresses
endometrial proliferation resulting in amenorrhea and relieves vasomotor symptoms. The use
of the LNG-IUS in perimenopausal women
seems to be well tolerated and associated with
a favorable bleeding pattern [66] . The LNG-IUS
is an off-label treatment used for menstrual
bleeding in the USA.
If polyps are the cause of irregular bleeding
they should be removed at hysteroscopy in order
to exclude hyperplasia or malignancy. This may
improve abnormal bleeding; however, this has
not been well studied. Endometrial polyps
mayrecur.
In cases in which irregular bleeding does
not respond to medical or more conservative
measures, or in cases in which women have
completed childbearing, surgery is an option.
Endometrial ablation, which involves destruction of the endometrium while leaving the uterus
insitu, is less invasive and leads to similar rates
of patient satisfaction as hysterectomy [67] .
Endometrial ablation is achieved by a variety of
mechanisms, the initial methods involved hysteroscopic use of the neodymium-doped yttrium
aluminium garnet laser; however, this method
evolved into the use of a resection loop or roller
ball to destroy the endometrium. Newer global
systems have been developed that use bipolar or
microwave energy, cryotherapy or hydrothermal
techniques. Most of these newer techniques are
easy to perform, take less time and do not require
general anesthesia. Many providers are moving
this procedure to the clinic and performing it in
an office setting, which is acceptable to many
patients [68] . Success with endometrial ablation
is high, with 8090% of patients reporting
reduced bleeding and 2550% achieving amenorrhea, depending on the technique used [69] .
Most women (7080%) report less menstrual
pain; however, up to a third of patients may
require reoperation within 5years [67] .
Hysterectomy achieves high levels of satisfaction but is associated with more perioperative
morbidity and is a poor choice for women with
medical conditions that significantly increase
the risks of surgery [67] . Before embarking on
hysterectomy, the risks of major surgery must be

Women's Health (2009) 5(3)

321

review Hickey, Karthigasu & Agarwal

weighed against the risks of alternative management. In properly selected patients, hysterectomy
may be the best choice.
Conclusion & future perspective

confused with the polycystic ovary of an adult

women with PCOS. A diagnostic criteria for
PCOS in adolescents is needed to correctly diagnose this disorder. In addition, futher studies are
needed to assess the safety of OCP in adolescents.

The underlying causes of AUB are poorly understood and this has considerably limited the development of medical treatment options. Further
studies are needed in this area to investigate the
underlying mechanisms so that the therapy can
be more targeted to the cause. Diagnostic criteria
for PCOS, particularly the clinical features (e.g.,
menstrual irregularity and acne) are considered
normal in adolescents and the multifollicular ovary of the normal adolescent also may be

Financial & competing interests disclosure

The authors have no relevant affiliations or financial
involvement with any organization or entity with a financial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties. No writing assistance was utilized in
the production of this manuscript.

Executive summary
Abnormal uterine bleeding
A confusing, inconsistent and overlapping array of terms has evolved to describe abnormal
frequency, duration or volume of uterine bleeding. For this reason, the general term
abnormal uterine bleeding is often used instead of terms such as polymenorrhea, menorrhagia
and oligomenorrhea.
Irregular menstrual bleeding can be either too frequent (a cycle of less than every 21days) or
infrequent (a cycle of more than every 36days).
Menstrual irregularities in adolescents under 20 years old
Irregular uterine bleeding in adolescent girls may result from a wide spectrum of conditions. The
most common cause is anovulation, which may be due to immaturity of hypothalamicpituitary
ovarian axis or polycystic ovary syndrome (PCOS).
Menstrual irregularity associated with normal reproductive development is likely to resolve within
the first 2years following menarche, but persistent menstrual irregularity in adolescence may be an
early presentation of PCOS.
All patients with dysfunctional uterine bleeding (DUB) are at risk for iron deficiency anemia and
should be treated. The decision of whether to observe girls with DUB or to treat them with
hormonal therapy depends upon patient and guardian considerations, as well as upon the severity
and chronicity of the DUB.
All patients with PCOS should be managed with supportive therapy that encourages lifestyle
changes, the maintenance of a healthy weight, exercise and diet. Oral contraceptive pills (OCPs) are
the first-line endocrine treatment for women with the dermatologic or menstrual abnormalities
of PCOS.
Menstrual irregularities in the reproductive age group: 2040 years
Pregnancy should be considered as a possible cause in any sexually active reproductive-aged
women. PCOS is the most common cause of irregular uterine bleeding in reproductive-aged
women, affecting approximately 6% of this population. Endocrine disorders may be associated
with hormonal changes that affect ovulation and cause irregular menstruation including thyroid
dysfunction and hyperprolatinemia.
Menstrual irregularity should be treated in patients with PCOS, since chronic anovulation is
associated with increased risk of developing endometrial hyperplasia and carcinoma. The major
treatment options for menstrual irregularity include progestin or OCPs.
Menstrual irregularities in perimenopausal women over 40 years old
Menstrual bleeding irregularities are a hallmark of the menopausal transition but raise concerns
about possible pregnancy, endometrial hyperplasia or gynecologic malignancy.
It is recommended that women with AUB, over the age of 45 years, should be investigated with
hysteroscopy and endometrial biopsy.
Anovulatory irregular bleeding requires endometrial protection with a combined OCP, the
levonorgestrel intrauterine system (LNG-IUS) or cyclic oral progestins. In cases in which persistent
bleeding does not respond to medical or more conservative measures then hysterectomy could be
considered, or conservative surgery, such as endometrical abation.

322

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Abnormal uterine bleeding: a focus on polycystic ovary syndrome

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Affiliations

Martha Hickey,
FRANZCOG, MBChB, MD, MRCOG
Professor of Gynaecology, School of Womens
& Infants Health, King Edward Memorial
Hospital, University of Western Australia,
Australia
Tel: +61 893 401 328
Fax: +61 893 813 031
mhickey@meddent.uwa.edu.au

Krish Karthigasu,
FRANZCOG, MBBS, MRCOG
Senior lecturer, School of Womens & Infants
Health, King Edward Memorial Hospital,
University of Western Australia, Australia
Tel.: +61 893 828 323
Fax: +61 893 818 296
krishkar@bigpond.net.au

Sweta Agarwal,
FRANZCOG, MBBS, MS(O&G)
Consultant Gynaecologist, PIVET Medical
Centre, 166-168 Cambridge Street,
Leederville, Perth, WA
Tel.: +61 894 225 400
drsweta.agarwal@yahoo.com

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